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Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Authors :
Yu Wen
Lihong Hu
Rupeng Dai
Junwei Wang
Liang Gao
Fengjun He
Di Kang
Lina Gao
Jian Liu
Jingxian Zhou
Xiaojing Chen
Source :
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 72-84 (2020)
Publication Year :
2020
Publisher :
Taylor & Francis Group, 2020.

Abstract

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.

Details

Language :
English
ISSN :
14756374 and 14756366
Volume :
35
Issue :
1
Database :
OpenAIRE
Journal :
Journal of Enzyme Inhibition and Medicinal Chemistry
Accession number :
edsair.doi.dedup.....616b6d0b4fcc3c0fc1bb3278213daceb